Exploring the Nasal Microbiome–Metabolite Axis as a Potential Therapeutic Target in Parkinson’s Disease-Associated Olfactory Dysfunction

Abstract Olfactory impairment is a common early non-motor feature of Parkinson’s disease (PD), often preceding motor symptoms by several years. However, the biological mechanisms underlying PD-associated olfactory dysfunction remain poorly understood. This study investigated the relationship between nasal microbiota, metabolites, and olfactory function in PD and explored potential therapeutic targets. A total of 66 participants, including PD patients and healthy controls, were enrolled. Nasal samples were analyzed using 16S rRNA sequencing and metabolomic profiling by GC-MS. An MPTP-induced PD mouse model was used to evaluate the effects of cholic acid supplementation. PD patients exhibited distinct alterations in nasal microbial composition and metabolic profiles, which were associated with olfactory dysfunction severity. Cholic acid showed potential as a candidate biomarker for PD-associated olfactory impairment (AUC > 0.97). In MPTP mice, cholic acid improved olfactory performance and increased TH expression in the olfactory bulb and substantia nigra, but did not significantly improve motor deficits or striatal dopaminergic neuron loss. These findings suggest a potential association between nasal microbiota-associated metabolic alterations and olfactory dysfunction in PD.